CN108101755B - Method for preparing chiral 4- (2-propargyl) phenol compound - Google Patents

Method for preparing chiral 4- (2-propargyl) phenol compound Download PDF

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CN108101755B
CN108101755B CN201611042335.5A CN201611042335A CN108101755B CN 108101755 B CN108101755 B CN 108101755B CN 201611042335 A CN201611042335 A CN 201611042335A CN 108101755 B CN108101755 B CN 108101755B
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CN108101755A (en
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胡向平
邵龙
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Dalian Institute of Chemical Physics of CAS
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    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
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Abstract

A method for preparing chiral 4- (2-propargyl) phenol compounds, which belongs to the field of organic synthesis. The invention relates to a method for synthesizing a chiral 4- (2-propargyl) phenol compound from an electron-rich phenol compound and a propargyl compound through a catalytic asymmetric Friedel-crafts reaction. The chiral copper catalyst is prepared with copper salt and chiral tridentate P, N, N-ligand in situ in various polar and non-polar solvents. The invention can conveniently synthesize various chiral 4- (2-propargyl) phenol compounds with substituent groups, and the enantiomeric excess percentage of the chiral 4- (2-propargyl) phenol compounds is as high as 95%. The method has the characteristics of simple operation, easily obtained raw materials, wide application range of the substrate, high enantioselectivity and the like.

Description

Method for preparing chiral 4- (2-propargyl) phenol compound
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a chiral 4- (2-propargyl) phenol compound by catalyzing asymmetric propargyl Friedel-crafts reaction of an electron-rich phenol compound and a propargyl alcohol ester compound by a catalyst system consisting of Cu/P, N, N-ligands.
Background
Carbon-carbon bond formation reactions are the most important reactions in organic synthetic chemistry, wherein friedel-crafts reaction is one of the most efficient methods for constructing carbon-carbon bonds directly linked with aromatic compounds, while asymmetric friedel-crafts alkylation provides a direct route for synthesizing chiral aryl derivatives [ (a) Olah, g.a.; khrisnamurti, r.; prakash, G.K.S.In Comprehensive Organic Synthesis, Vol.3, Pergamon, New York,1991, pp.293-339 (b) Sheng, Y.F.; gu, q.; zhang, a.j.; you, s.l.j.org.chem.2009,74,6899.(c) Itoh, j.; fucibe, k.; akiyama, t.angelw.chem., int.ed.2008,47,4016 ]. However, the asymmetric friedel-crafts reaction develops relatively slowly, and until the last decade some important advances have been made [ (a) Wang, y; ding, k.chi.j.org.chem.2001, 21,763, (b) Wang, y.; ding, k.; dai, l.chemtracs 2001,14,610.(c) Bandini, m.; melloni, a.; Umani-Ronchi, a.angelw.chem.int.ed.2004, 43,550 ].
Since the terminal acetylenic bond can be converted into a variety of functional groups by simple reactions, the propargyl skeleton has become a reaction intermediate that is very common in organic conversion processes [ (a) Kolb, h.c.; sharpless, k.b. drug discov.today 2003,8,1128.(b) Meldal, m.;
Figure BDA0001160719670000011
C.W.Chem.Rev.2008,108,2952.(c)Hawker,C.J.；Wooley,K.L.Science 2005,309,1200.(d)Lallana,E.；Riguera,R.；Fernandez-Megia,E.Angew.Chem.,Int.Ed.2011,50,8794.]. Thus, the asymmetric Friedel-crafts reaction is realized by the asymmetric propargyl substitution reactionThe relevant research of gram reaction has important significance.
To date, few reports have been made on the achievement of an asymmetric friedel-crafts reaction by propargyl substitution. In 2009, the research group of ChanWai Hong, university of southern ocean science and technology, singapore, reported that indenol was synthesized by ytterbium catalyzed serial friedel-crafts reaction/aromatic hydrogenation reaction of propargyl alcohol and phenol, and the indenol and derivatives thereof were synthesized in one step under mild conditions, with enantioselectivity reaching 99% ee [ Zhang, x. -x.; teo, w. -t.; chan, w. -h.org.lett.2009,11,21 ]. The chiral propargyl substituted phenol compounds synthesized by catalyzing asymmetric propargyl Friedel-crafts reaction are not reported in documents.
The invention realizes the asymmetric propargyl Friedel-crafts reaction of the electron-rich phenol compound and the propargyl alcohol ester compound by utilizing the catalyst consisting of the self-developed metallic copper/P, N, N-ligand, and can synthesize the chiral 4- (2-propargyl) phenol compound with high efficiency and high enantioselectivity.
Disclosure of Invention
The invention aims to provide a method for synthesizing a chiral 4- (2-propargyl) phenol compound by copper-catalyzed electron-rich phenol compound and propargyl compound through asymmetric propargyl Friedel-crafts reaction. The method has the characteristics of easily obtained raw materials, simple operation, high enantioselectivity and the like.
The invention provides a method for preparing chiral 4- (2-propargyl) phenol compounds, which is characterized in that under the existence of an alkali additive, a chiral copper catalyst catalyzes an electron-rich phenol compound and a propargyl compound to synthesize the compounds through an asymmetric propargyl Friedel-crafts reaction in a reaction medium, and the method comprises the following specific steps:
(1) preparation of chiral copper catalyst: under the protection of nitrogen, copper salt and P, N, N-ligand are stirred in a reaction medium for 0.5 to 2 hours according to the molar ratio of 1:0.1 to 10 to prepare a chiral copper catalyst;
(2) preparation of chiral 4- (2-propargyl) phenol compound: dissolving an electron-rich phenol compound, a propargyl compound and an alkali additive in a reaction medium, and then adding the solution into the stirred solution of the chiral copper catalyst under the protection of nitrogen, and stirring and reacting for 1-12 hours at the temperature of-20 ℃; after the reaction is finished, performing reduced pressure rotary evaporation and column separation to obtain a chiral para-propargyl phenol compound;
the molar ratio of the chiral copper catalyst to the propargyl compound is 0.001-1: 1;
the molar ratio of the alkali additive to the propargyl compound is 0.5-10: 1;
the molar ratio of the electron-rich phenol compound to the propargyl compound is 1-2: 1.
the reaction medium is at least one of methanol, ethanol, toluene, xylene, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran and ethyl acetate.
The chiral 4- (2-propargyl) phenol compound has one of the following structures:
Figure BDA0001160719670000021
i and II are enantiomers of each other, wherein: r1、R2Is C1-C40 alkyl, C3-C12 cycloalkyl or C3-C12 cycloalkyl with substituent, phenyl and substituted phenyl, benzyl and substituted benzyl, five-membered or six-membered heterocyclic aromatic group or ester group containing one or more than two oxygen, sulfur and nitrogen atoms; the substituent of the C3-C12 naphthenic base, the substituent of the phenyl or the substituent of the benzyl is C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano respectively.
The phenolic compound has the following structure:
Figure BDA0001160719670000022
in the formula: r1Is the same as R in the structural formula I, II1The same groups.
The propargyl compound has the following structure:
Figure BDA0001160719670000023
in the formula: r2Is represented by the structural formula R in I, II2The same group; x is fluorine, chlorine, bromine, iodine, alkyl carboxylate, alkyl carbonate, alkyl sulfonate, alkyl phosphate, phenyl and substituted phenyl carboxylate, phenyl and substituted phenyl carbonate, phenyl and substituted phenyl sulfonate or phenyl and substituted phenyl phosphate.
The copper salt is hydrated copper acetate, hydrated copper sulfate, anhydrous copper acetate, anhydrous copper sulfate, copper triflate, copper chloride, cuprous acetate, cuprous chloride, cuprous iodide, cuprous perchlorate, copper triflate, Cu (CH)3CN)4BF4、Cu(CH3CN)4ClO4At least one of (1). Preferably hydrated copper acetate, trifluomethane sulfonate, Cu (CH)3CN)4BF4、Cu(CH3CN)4ClO4At least one of (1).
The structural formula of the chiral P, N, N-ligand is as follows:
Figure BDA0001160719670000031
in the formula: r3，R4Is alkyl in H, C1-C10, cycloalkyl in C3-C8, phenyl and substituted phenyl or benzyl and substituted benzyl;
R5，R6is H, halogen, alkyl and cycloalkyl, phenyl and substituted phenyl, alkoxy, phenoxy, acyl or nitro;
R7is alkyl, cycloalkyl, phenyl and substituted phenyl, naphthyl and substituted naphthyl or a five-membered or six-membered heterocyclic aromatic group containing one or more oxygen, sulfur and nitrogen atoms.
The base additive is various inorganic bases or organic bases, preferably N, N-diisopropylethylamine, triethylamine, DBU, K3PO4、K2CO3、Cs2CO3、Na2CO3Or NaHCO3。
The catalytic reaction conditions in the step (2) are preferably as follows: the temperature is-20 ℃; the reaction medium is methanol; the pressure is normal pressure; the time period required was 12 hours.
The molar ratio of the chiral copper catalyst to the propargyl compound is preferably 0.01-0.1: 1;
the molar ratio of the alkali additive to the propargyl compound is preferably 1.2: 1;
the molar ratio of the phenol compound to the propargyl compound is preferably 1.2: 1.
The reaction equation of the invention is as follows:
Figure BDA0001160719670000032
the invention has the following advantages:
1. the starting materials are cheap and easy to obtain.
2. The chiral ligand is simple and convenient to synthesize, the catalyst is cheap and easy to obtain, and the dosage is small.
3. Good reaction activity and high stereoselectivity.
4. The method can conveniently synthesize various substituted chiral 4- (2-propargyl) phenol compounds by using an asymmetric catalysis method for the first time.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of (S) -3, 5-dimethoxy-4- (1-phenyl-2-propargyl) phenol I-1 prepared in example 1;
FIG. 2 is a carbon nuclear magnetic resonance spectrum of (S) -3, 5-dimethoxy-4- (1-phenyl-2-propargyl) phenol I-1 prepared in example 1;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of (S) -3, 5-dimethoxy-4- (1-p-chlorophenyl-2-propargyl) -phenol I-2 prepared in example 9;
FIG. 4 is a NMR carbon spectrum of (S) -3, 5-dimethoxy-4- (1-p-chlorophenyl-2-propargyl) -phenol I-2 prepared in example 9;
FIG. 5 is a NMR hydrogen spectrum of (S) -3, 5-dimethoxy-4- (1-p-fluorophenyl-2-propargyl) -phenol I-3 prepared in example 10;
FIG. 6 is a NMR carbon spectrum of (S) -3, 5-dimethoxy-4- (1-p-fluorophenyl-2-propargyl) -phenol I-3 prepared in example 10;
FIG. 7 is a NMR hydrogen spectrum of (S) -3, 5-dimethoxy-4- (1-p-methoxyphenyl-2-propargyl) -phenol I-4 prepared in example 11;
FIG. 8 is a NMR carbon spectrum of (S) -3, 5-dimethoxy-4- (1-p-methoxyphenyl-2-propargyl) -phenol I-4 prepared in example 11;
FIG. 9 is a NMR spectrum of (S) -3, 5-dimethoxy-4- (1-naphthyl-2-propargyl) -phenol I-5 prepared in example 12;
FIG. 10 is a NMR carbon spectrum of the product (S) -3, 5-dimethoxy-4- (1-naphthyl-2-propargyl) -phenol I-5 prepared in example 12;
FIG. 11 is a NMR spectrum of (S) -3, 5-dimethoxy-4- (1-o-chlorophenyl-2-propargyl) -phenol I-6 prepared in example 13;
FIG. 12 is a NMR carbon spectrum of (S) -3, 5-dimethoxy-4- (1-o-chlorophenyl-2-propargyl) -phenol I-6 prepared in example 13;
FIG. 13 is a NMR spectrum of (S) -3, 5-dimethoxy-4- (1-p-methylphenyl-2-propargyl) -phenol I-7 prepared in example 14;
FIG. 14 is a NMR carbon spectrum of (S) -3, 5-dimethoxy-4- (1-p-methylphenyl-2-propargyl) -phenol I-7 prepared in example 14;
Detailed Description
The following examples further illustrate the invention but are not intended to limit the invention thereto. NMR was measured by Bruker400M NMR spectrometer and High Performance Liquid Chromatography (HPLC) was measured by Agilent 1100 series high performance liquid chromatography.
Example 1
Cu(OAc)2.H2And catalyzing and reacting the O and the L-2-1 serving as catalysts to generate a product (S) -3, 5-dimethoxy-4- (1-phenyl-2-propargyl) phenol I-1.
Adding Cu (OAc)2.H2O (0.015mmol, 5 mol%) and chiral ligand L-2-1(0.0165mmol, 5.5 mol%), adding 1.0 ml of anhydrous methanol under the protection of nitrogen, and stirring at room temperature for 1 hour. Mixing propargyl alcohol ester IV-1 (0.3mmol, 1equiv),3, 5-dimethylOxyphenol III-1 (0.36mmol, 1.2equiv) and N, N-diisopropylethylamine (0.36mmol, 1.2equiv) were dissolved in 2.0 ml of anhydrous methanol, and the solution was added to the stirred solution of the catalyst under nitrogen protection, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was rotary-distilled under reduced pressure to about 0.5 ml, separated by silica gel column (petroleum ether/ethyl acetate: 5:1), concentrated under reduced pressure, and dried in vacuo to give compound i-1 as a pale yellow oil in 82% yield and 87% ee.
The hydrogen nuclear magnetic resonance spectrum and the carbon nuclear magnetic resonance spectrum of (S) -3, 5-dimethoxy-4- (1-phenyl-2-propargyl) phenol I-1 are respectively shown in the following figures 1 and 2:
1H NMR(400MHz,DMSO):δ9.53(s,1H),7.34(d,J＝7.6Hz,2H),7.26(d,J＝7.5Hz,2H),7.15(t,J＝7.1Hz,1H),6.10(s,2H),5.50(s,1H),3.66(s,6H),2.97(d,J＝0.7Hz,1H).13C NMR(101MHz,DMSO):δ158.8,158.5,141.4,128.2,127.4,126.3,108.3,93.0,85.0,71.8,56.0,30.5.HPLC(Chiralcel AD-H,n-hexane/i-PrOH＝70/30,0.8ml/min,230nm,40℃):tR(major)＝8.7min,tR(minor)＝10.0min。
the structural formula of III-1, IV-1, I-1, L-2-1 is as follows:
Figure BDA0001160719670000051
example 2
L-2-2 is used as a ligand to prepare (S) -3, 5-dimethoxy-4- (1-phenyl-2-propargyl) phenol I-1.
The ligand L-2-1 in example 1 was replaced with ligand L-2-2, and the procedure was otherwise the same as in example 1. The reaction gave compound II-2 in 51% yield and 62% ee.
The structural formula of L-2-2 is as follows:
Figure BDA0001160719670000052
example 3
L-2-3 is used as a ligand to prepare (R) -3, 5-dimethoxy-4- (1-phenyl-2-propargyl) phenol II-1.
The ligand L-2-1 in example 1 was replaced with ligand L-2-3, and the procedure was otherwise the same as in example 1. The reaction gave compound II-1 in 22% yield and 52% ee.
The structural formula of L-2-3, II-1 is as follows:
Figure BDA0001160719670000061
example 4
NEt3(S) -3, 5-dimethoxy-4- (1-phenyl-2-propargyl) phenol I-1 was prepared as a base.
The base N, N-diisopropylethylamine from example 1 was used with NEt3Instead, the rest is the same as example 1. The reaction gave compound I-1 in 55% yield and 87% ee.
Example 5
K2CO3(S) -3, 5-dimethoxy-4- (1-phenyl-2-propargyl) phenol I-1 was prepared as a base.
The base N, N-diisopropylethylamine from example 1 was substituted with K2CO3Instead, the rest is the same as example 1. The reaction gave compound I-1 in 93% yield and 87% ee.
Example 6
Cu(OTf)2And L-2-1 is used as a catalyst to catalyze and react to generate a product (S) -3, 5-dimethoxy-4- (1-phenyl-2-propargyl) phenol I-1.
Cu (OAc) in example 52·H2Replacement of O by Cu (OTf)2. The remainder of the procedure is as in example 5 to give compound I-1 in 84% yield and 88% ee.
Example 7
Cu(OTf)·1/2C6H6And L-2-1 is used as a catalyst to catalyze and react to generate a product (S) -3, 5-dimethoxy-4- (1-phenyl-2-propargyl) phenol I-1.
Cu (OAc) in example 52·H2Replacement of O by Cu (OTf) 1/2C6H6. The remainder of the procedure is as in example 5 to give compound I-1 in 67% yield and 85% ee.
Example 8
The reaction at-20 ℃ produces the product (S) -3, 5-dimethoxy-4- (1-phenyl-2-propargyl) phenol I-1.
The reaction temperature in example 6 was changed to-20 ℃. The remainder of the procedure is as in example 6 to give compound I-1 in 96% yield and 93% ee.
Example 9
Propargyl alcohol ester IV-2 is used as a substrate to react to generate a product (S) -3, 5-dimethoxy-4- (1-p-chlorophenyl-2-propargyl) -phenol I-2.
The procedure in example 8 was repeated except for substituting propargyl alcohol ester IV-1 in example 8 with IV-2 to give the compound (S) -3, 5-dimethoxy-4- (1-p-chlorophenyl-2-propargyl) -phenoxide I-2 in 88% yield and 92% ee.
The hydrogen nuclear magnetic resonance spectrum and the carbon nuclear magnetic resonance spectrum of (S) -3, 5-dimethoxy-4- (1-p-chlorophenyl-2-propargyl) -phenol I-2 are respectively shown in the following figures 3 and 4:
1H NMR(400MHz,DMSO):δ9.56(s,1H),7.31(s,4H),6.10(s,2H),5.47(s,1H),3.66(s,6H),3.04(s,1H).13C NMR(101MHz,DMSO):δ159.0,158.4,140.4,130.9,129.2,128.2,107.8,93.0,84.5,72.3,56.0,30.0.HPLC(Chiralcel AD-H,n-hexane/i-PrOH＝85/15,0.8ml/min,230nm,40℃):tR(major)＝13.8min,tR(minor)＝15.2min。
the structural formula of IV-2 and I-2 is as follows:
Figure BDA0001160719670000071
example 10
Propargyl alcohol ester IV-3 is used as a substrate to react to generate a product (S) -3, 5-dimethoxy-4- (1-p-fluorophenyl-2-propargyl) -phenol I-3.
The procedure in example 8 was repeated except for substituting propargyl alcohol ester IV-1 in example 8 with IV-3 to give the compound (S) -3, 5-dimethoxy-4- (1-p-fluorophenyl-2-propargyl) -phenoxide I-3 in 90% yield and 90% ee.
The hydrogen nuclear magnetic resonance spectrum and the carbon nuclear magnetic resonance spectrum of the product (S) -3, 5-dimethoxy-4- (1-p-fluorophenyl-2-propargyl) -phenol I-3 are respectively shown in the following figures 5 and 6:
1H NMR(400MHz,DMSO):δ9.54(s,1H),7.33(s,2H),7.08(d,J＝8.9Hz,2H),6.09(s,2H),5.46(s,1H),3.66(s,6H),3.01(d,J＝2.3Hz,1H).13C NMR(101MHz,DMSO):δ161.0(d,J＝241.7Hz),158.8,158.4,137.5(d,J＝2.9Hz),129.1(d,J＝8.1Hz),115.0,114.8,108.1,93.0,84.8,72.1,56.0,29.9.HPLC(Chiralcel AD-H,n-hexane/i-PrOH＝90/10,0.8ml/min,230nm,40℃):tR(major)＝20.1min,tR(minor)＝21.8min。
the structural formula of IV-3 and I-3 is as follows:
Figure BDA0001160719670000072
example 11
Propargyl alcohol ester IV-4 is used as a substrate to react to generate a product (S) -3, 5-dimethoxy-4- (1-p-methoxyphenyl-2-propargyl) -phenol I-4.
The procedure in example 8 was repeated except for substituting propargyl alcohol ester IV-1 in example 8 with IV-4 to give the compound (S) -3, 5-dimethoxy-4- (1-p-methoxyphenyl-2-propargyl) -phenoi-4 in 89% yield and 97% ee.
The hydrogen nuclear magnetic resonance spectrum and the carbon nuclear magnetic resonance spectrum of (S) -3, 5-dimethoxy-4- (1-p-methoxyphenyl-2-propargyl) -phenol I-4 are respectively shown in the following figures 7 and 8:
1H NMR(400MHz,DMSO):δ9.50(s,1H),7.24(d,J＝8.3Hz,2H),6.81(d,J＝8.5Hz,2H),6.09(s,2H),5.43(s,1H),3.68(d,J＝12.1Hz,9H),2.94(d,J＝1.7Hz,1H).13C NMR(101MHz,DMSO):δ158.6,158.4,157.9,133.3,128.4,113.6,108.6,93.0,85.4,71.5,56.0,55.4,29.7.HPLC(Chiralcel AD-H,n-hexane/i-PrOH＝80/20,0.8ml/min,230nm,40℃):tR(minor)＝20.7min,tR(major)＝26.3min。
the structural formula of IV-4 and I-4 is as follows:
Figure BDA0001160719670000081
example 12
Propargyl alcohol ester IV-5 is used as a substrate to react to generate a product (S) -3, 5-dimethoxy-4- (1-naphthyl-2-propargyl) -phenol I-5.
The procedure in example 8 was repeated except for substituting propargyl alcohol ester IV-1 in example 8 with IV-5 to give the compound (S) -3, 5-dimethoxy-4- (1-naphthyl-2-propargyl) -phenoxide I-5 in 84% yield and 93% ee.
The hydrogen nuclear magnetic resonance spectrum and the carbon nuclear magnetic resonance spectrum of the product (S) -3, 5-dimethoxy-4- (1-naphthyl-2-propargyl) -phenol I-5 are respectively shown in the following figures 9 and 10:
1H NMR(400MHz,DMSO):δ9.56(s,1H),8.05–7.73(m,4H),7.44(dd,J＝13.4,7.1Hz,3H),6.12(s,2H),5.67(s,1H),3.67(s,6H),3.10(d,J＝2.5Hz,1H).13C NMR(101MHz,DMSO)δ158.9,158.6,139.0,133.2,132.1,128.0,127.8,127.7,126.5,126.4,125.8,125.3,108.1,93.0,84.9,72.4,56.1,30.7.HPLC(Chiralcel AD-H,n-hexane/i-PrOH＝80/20,0.8ml/min,230nm,40℃):tR(major)＝8.8min,tR(minor)＝10.1min。
the structural formula of IV-5 and I-5 is as follows:
Figure BDA0001160719670000082
example 13
Propargyl alcohol ester IV-6 is used as a substrate to react to generate a product (S) -3, 5-dimethoxy-4- (1-o-chlorophenyl-2-propargyl) -phenol I-6.
The procedure in example 8 was repeated except for substituting propargyl alcohol ester IV-1 in example 8 with IV-6 to give the compound (S) -3, 5-dimethoxy-4- (1-o-chlorophenyl-2-propargyl) -phenoi-6 in 86% yield and 76% ee.
The hydrogen nuclear magnetic resonance spectrum and the carbon nuclear magnetic resonance spectrum of the product (S) -3, 5-dimethoxy-4- (1-o-chlorophenyl-2-propargyl) -phenol I-6 are respectively shown in the following figures 11 and 12:
1H NMR(400MHz,DMSO):δ9.53(d,J＝4.6Hz,1H),7.86(d,J＝6.6Hz,1H),7.31(t,J＝7.9Hz,2H),7.22(d,J＝7.6Hz,1H),6.06(d,J＝6.8Hz,2H),5.62(dd,J＝8.4,2.4Hz,1H),3.62(d,J＝2.8Hz,6H),3.05(d,J＝2.7Hz,1H).13C NMR(101MHz,DMSO):δ159.0,158.8,138.2,132.5,131.8,129.4,128.5,126.5,106.3,93.0,84.4,72.4,55.9,29.6.HPLC(Chiralcel AD-H,n-hexane/i-PrOH＝80/20,0.8ml/min,230nm,40℃):tR(major)＝8.7min,tR(minor)＝10.3min。
the structural formula of IV-6 and I-6 is as follows:
Figure BDA0001160719670000091
example 14
Propargyl alcohol ester IV-7 is used as a substrate to react to generate a product (S) -3, 5-dimethoxy-4- (1-p-methylphenyl-2-propargyl) -phenol I-7.
The procedure in example 8 was repeated except for substituting propargyl alcohol ester IV-1 in example 8 with IV-7 to give the compound (S) -3, 5-dimethoxy-4- (1-p-methylphenyl-2-propargyl) -phenoi-7 in 90% yield and 93% ee.
The hydrogen nuclear magnetic resonance spectrum and the carbon nuclear magnetic resonance spectrum of the product (S) -3, 5-dimethoxy-4- (1-p-methylphenyl-2-propargyl) -phenol I-7 are respectively shown in the following figures 13 and 14:
1H NMR(400MHz,DMSO):δ9.50(s,1H),7.20(d,J＝8.0Hz,2H),7.04(d,J＝8.0Hz,2H),6.08(s,2H),5.43(d,J＝2.1Hz,1H),3.65(s,6H),2.95(d,J＝2.7Hz,1H),2.24(s,3H).13C NMR(101MHz,DMSO):δ158.6,158.4,138.3,135.2,128.8,127.3,108.4,92.9,85.2,71.7,56.0,30.1,21.0.HPLC(Chiralcel AD-H,n-hexane/i-PrOH＝90/10,0.8ml/min,230nm,40℃):tR(major)＝17.4min,tR(minor)＝18.9min。
the structural formulas of IV-7 and I-7 are as follows:
Figure BDA0001160719670000092
examples 15 to 25
Reaction substrate suitability
The method has wide substrate applicability, and a plurality of substrates can participate in the reaction according to the reaction conditions in the example 8, so that the chiral 4- (1-phenyl-2-propargyl) -phenol compound can be obtained with high yield and high stereoselectivity, and the reaction formula is as follows:
Figure BDA0001160719670000101
in examples 15 to 25, when R is1And R2Respectively, and the yields and enantiomeric excess values thereof are shown in table 1.
TABLE 1
Figure BDA0001160719670000102
The invention can conveniently synthesize various chiral 4- (2-propargyl) phenol compounds with substituent groups, and the enantiomeric excess percentage of the chiral 4- (2-propargyl) phenol compounds is as high as 95%. The method has the characteristics of simple operation, easily obtained raw materials, wide application range of the substrate, high enantioselectivity and the like.

Claims (9)

1. A method for preparing chiral 4- (2-propargyl) phenol compounds, which is characterized by comprising the following steps: in the presence of an alkali additive, catalyzing an electron-rich phenol compound and a propargyl compound in a reaction medium by a chiral copper catalyst to synthesize a chiral 4- (2-propargyl) phenol compound through an asymmetric Friedel-crafts reaction;
the preparation of the chiral copper catalyst comprises the following steps: under the protection of nitrogen, copper salt and chiral P, N, N-ligand are stirred in a reaction medium for 0.5 to 2 hours according to the molar ratio of 1:0.1 to 1:10 to prepare a chiral copper catalyst;
the chiral 4- (2-propargyl) phenol compound has one of the following two structures:
Figure 922848DEST_PATH_IMAGE001
i and II are each an enantiomer, in which R1、R2Is C1-C40 alkyl, C3-C12 cycloalkyl, substitutedC3-C12 cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, one or more five-membered or six-membered heterocyclic aromatic groups containing one or more than two oxygen, sulfur or nitrogen atoms, or ester groups;
the electron-rich phenolic compound has the following structure:
Figure 167884DEST_PATH_IMAGE002
in the formula, R1Is one or more than two of C1-C40 alkyl, C3-C12 cycloalkyl, C3-C12 cycloalkyl with substituent, phenyl, substituted phenyl, benzyl, substituted benzyl, five-membered or six-membered heterocyclic aromatic groups or ester groups containing one or more than two oxygen, sulfur or nitrogen atoms;
the substituent on the C3-C12 naphthenic base, the substituent on the phenyl and the substituent on the benzyl are respectively one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano;
the structural formula of the chiral P, N, N-ligand is as follows:
Figure 275518DEST_PATH_IMAGE003
；
in the formula, R3，R4Is one or more than two of alkyl in H, C1-C10, cycloalkyl in C3-C8, phenyl, substituted phenyl, benzyl or substituted benzyl; the substituent on the substituted phenyl or the substituted benzyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5;
R5，R6is one or more than two of H, halogen, C1-C10 alkyl, C3-C8 cycloalkyl, phenyl, substituted phenyl, C1-C40 alkoxy, phenoxy, acyl or nitro; the substituent on the substituted phenyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano,the number of the substituent groups is 1-5;
R7is C1-C10 alkyl, C3-C8 cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl or one or more five-membered or six-membered heterocyclic aromatic groups containing one or more than two oxygen, sulfur and nitrogen atoms; the substituent on the substituted phenyl or the substituted naphthyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.
2. A process for the preparation of chiral 4- (2-propargyl) phenol compounds according to claim 1, wherein:
the method comprises the following specific steps:
(1) preparation of chiral copper catalyst: under the protection of nitrogen, copper salt and chiral P, N, N-ligand are stirred in a reaction medium for 0.5 to 2 hours according to the molar ratio of 1:0.1 to 1:10 to prepare a chiral copper catalyst;
(2) preparation of chiral 4- (2-propargyl) phenol compound: dissolving an electron-rich phenol compound, a propargyl compound and an alkali additive in a reaction medium, and then adding the solution into the solution of the chiral copper catalyst prepared in the step (1) under the protection of nitrogen, and stirring and reacting for 1-12 hours at the temperature of-40 ℃; performing reduced pressure rotary evaporation and column separation to obtain a chiral 4- (2-propargyl) phenol compound;
the molar ratio of the chiral copper catalyst to the propargyl compound in the step (2) is 0.001: 1-1: 1; the molar ratio of the alkali additive to the propargyl compound is 0.5: 1-10: 1;
the molar ratio of the electron-rich phenol compound to the propargyl compound is 1: 1-2: 1.
3. a process according to claim 1 for the preparation of chiral 4- (2-propargyl) phenol compounds, characterized in that:
the substituent on the C3-C12 naphthenic base, the substituent on the phenyl and the substituent on the benzyl are respectively one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano.
4. A process for the preparation of chiral 4- (2-propargyl) phenol compounds according to claim 1 or 2, wherein: the reaction medium is one or more than two of methanol, ethanol, toluene, benzene, xylene, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran or ethyl acetate.
5. A process for the preparation of chiral 4- (2-propargyl) phenol compounds according to claim 2, wherein:
the propargyl compound has the following structure:
Figure 873989DEST_PATH_IMAGE004
in the formula, R2Is one or more than two of C1-C40 alkyl, C3-C12 cycloalkyl, C3-C12 cycloalkyl with substituent, phenyl, substituted phenyl, benzyl, substituted benzyl, five-membered or six-membered heterocyclic aromatic groups or ester groups containing one or more than two oxygen, sulfur or nitrogen atoms;
the substituent on the C3-C12 naphthenic base, the substituent on the phenyl and the substituent on the benzyl are respectively one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano; x is one or more than two of fluorine, chlorine, bromine, iodine, alkyl carboxylic ester, alkyl carbonic ester, alkyl sulfonic ester, alkyl phosphate, phenyl and substituted phenyl carboxylic ester, phenyl and substituted phenyl carbonic ester, phenyl and substituted phenyl sulfonic ester or phenyl and substituted phenyl phosphate; the substituent on the substituted phenyl is one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano, and the number of the substituent is 1-5.
6. A process for the preparation of chiral 4- (2-propargyl) phenol compounds according to claim 2, wherein: the copper salt is hydrated copper acetate and hydrated sulfurCupric acetate, anhydrous cupric sulfate, copper trifluoromethanesulfonate, cupric chloride, cuprous acetate, cuprous chloride, cuprous iodide, cuprous perchlorate, copper trifluoromethanesulfonate, Cu (CH)3CN)4BF4Or Cu (CH)3CN)4ClO4One or more than two of them.
7. A process for the preparation of chiral 4- (2-propargyl) phenol compounds according to claim 1 or 2, wherein: the alkali additive is one or more of various inorganic bases or organic bases, and is N, N-diisopropylethylamine, triethylamine, DBU, K3PO4、K2CO3、Cs2CO3、Na2CO3Or NaHCO3One or more than two of them.
8. A process for the preparation of chiral 4- (2-propargyl) phenol compounds according to claim 2, wherein: the catalytic reaction conditions in the step (2) are as follows: the temperature is-20 ℃; the reaction medium is methanol; the pressure is normal pressure; the time period required was 12 hours.
9. A process for the preparation of chiral 4- (2-propargyl) phenol compounds according to claim 2, wherein:
the molar ratio of the chiral copper catalyst to the propargyl compound is preferably 0.01-0.1: 1;
the molar ratio of the alkali additive to the propargyl compound is preferably 1.2: 1;
the molar ratio of the phenol compound to the propargyl compound is preferably 1.2: 1;
the copper salt is preferably one or more of hydrated copper acetate, copper trifluoromethanesulfonate, cuprous chloride and cuprous iodide;
the reaction medium is preferably one or two of methanol, ethanol and dichloromethane.
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